Amino-substituted imidazopyridazines

ABSTRACT

The present invention relates to amino-substituted imidazopyridazine compounds of general formula (I), in which A, R1, R2, R3, R4, R5 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

The present invention relates to amino-substituted imidazopyridazinecompounds of general formula (I) as described and defined herein, tomethods of preparing said compounds, to intermediate compounds usefulfor preparing said compounds, to pharmaceutical compositions andcombinations comprising said compounds and to the use of said compoundsfor manufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of a hyper-proliferative and/orangiogenesis disorder, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit MKNK1kinase (also known as MAP Kinase interacting Kinase, Mnk1) and MKNK2kinase (also known as MAP Kinase interacting Kinase, Mnk2). Human MKNKscomprise a group of four proteins encoded by two genes (Gene symbols:MKNK1 and MKNK2) by alternative splicing. The b-forms lack a MAPkinase-binding domain situated at the C-terminus. The catalytic domainsof the MKNK1 and MKNK2 are very similar and contain a unique DFD(Asp-Phe-Asp) motif in subdomain VII, which usually is DFG (Asp-Phe-Gly)in other protein kinases and suggested to alter ATP binding [Jauch etal., Structure 13, 1559-1568, 2005 and Jauch et al., EMBO J25,4020-4032, 2006]. MKNK1a binds to and is activated by ERK and p38 MAPKinases, but not by JNK1. MKNK2a binds to and is activated only by ERK.MKNK1 b has low activity under all conditions and MKNK2b has a basalactivity independent of ERK or p38 MAP Kinase. [Buxade M et al.,Frontiers in Bioscience 5359-5374, May 1, 2008]

MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E(eIF4E), heterogeneous nuclear RNA-binding protein A1 (hnRNP A1),polypyrimidine-tract binding protein-associated splicing factor (PSF),cytoplasmic phospholipase A2 (cPLA2) and Sprouty 2 (hSPRY2) [Buxade M etal., Frontiers in Bioscience 5359-5374, May 1, 2008].

eIF4E is an oncogene that is amplified in many cancers and isphosphorylated exclusively by MKNKs proteins as shown by KO-mousestudies [Konicek et al., Cell Cycle 7:16, 2466-2471, 2008; Ueda et al.,Mol Cell Biol 24, 6539-6549, 2004]. eIF4E has a pivotal role in enablingthe translation of cellular mRNAs. eIF4E binds the 7-methylguanosine capat the 5′ end of cellular mRNAs and delivers them to the ribosome aspart of the eIF4F complex, also containing eIF4G and eIF4A. Though allcapped mRNAs require eIF4E for translation, a pool of mRNAs isexceptionally dependent on elevated eIF4E activity for translation.These so-called “weak mRNAs” are usually less efficiently translated dueto their long and complex 5′ UTR region and they encode proteins thatplay significant roles in all aspects of malignancy including VEGF,FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparanase, etc.Expression and function of eIF4E is elevated in multiple human cancersand directly related to disease progression [Konicek et al., Cell Cycle7:16, 2466-2471, 2008].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E atSer209. Overall translation rates are not affected by eIF4Ephosphorylation, but it has been suggested that eIF4E phosphorylationcontributes to polysome formation (i.e. multiple ribosome on a singlemRNA) that ultimately enables more efficient translation of “weak mRNAs”[Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008].Alternatively, phosphorylation of eIF4E by MKNK proteins mightfacilitate eIF4E release from the 5′ cap so that the 48S complex canmove along the “weak mRNA” in order to locate the start codon [Blagden SP and Willis A E, Nat Rev Clin Oncol. 8(5):280-91, 2011]. Accordingly,increased eIF4E phosphorylation predicts poor prognosis in non-smallcell lung cancer patients [Yoshizawa et al., Clin Cancer Res.16(1):240-8, 2010]. Further data point to a functional role of MKNK1 incarcinogenesis, as overexpression of constitutively active MKNK1, butnot of kinase-dead MKNK1, in mouse embryo fibroblasts accelerates tumorformation [Chrestensen C. A. et al., Genes Cells 12, 1133-1140, 2007].Moreover, increased phosphorylation and activity of MKNK proteinscorrelate with overexpression of HER2 in breast cancer [Chrestensen, C.A. et al., J. Biol. Chem. 282, 4243-4252, 2007]. Constitutively active,but not kinase-dead, MKNK1 also accelerated tumor growth in a modelusing Eμ-Myc transgenic hematopoietic stem cells to produce tumors inmice. Comparable results were achieved, when an eIF4E carrying a S209Dmutation was analyzed. The S209D mutation mimicks a phosphorylation atthe MKNK1 phosphorylation site. In contrast a non-phosphorylatable formof eIF4E attenuated tumor growth [Wendel H G, et al., Genes Dev.21(24):3232-7, 2007]. A selective MKNK inhibitor that blocks eIF4Ephosphorylation induces apoptosis and suppresses proliferation and softagar growth of cancer cells in vitro. This inhibitor also suppressesoutgrowth of experimental B16 melanoma pulmonary metastases and growthof subcutaneous HCT116 colon carcinoma xenograft tumors withoutaffecting body weight [Konicek et al., Cancer Res. 71(5):1849-57, 2011].In summary, eIF4E phosphorylation through MKNK protein activity canpromote cellular proliferation and survival and is critical formalignant transformation. Inhibition of MKNK activity may provide atractable cancer therapeutic approach.

WO 2007/025540 A2 (Bayer Schering Pharma AG) relates to substitutedimidazo[1,2-b]pyridazines as kinase inhibitors, particularly PKC(protein kinase C) inhibitors, in particular PKC theta inhibitors.

WO 2007/025090 A2 (Kalypsis, Inc.) relates to heterocyclic compoundsuseful as inhibitors of Mitogen-activated protein kinase(MAPK)/Extracellular signal-regulated protein kinase (Erk) Kinase(abbreviated to “MEK”). In particular, WO 2007/025090 A2 relates interalia to imidazo[1,2-b]pyridazines.

WO 2007/013673 A1 (Astellas Pharma Inc.) relates to fused heterocyclesas inhibitors of Lymphocyte protein tyrosine kinase (abbreviated to“LCK”). In particular, WO 2007/013673 A1 relates inter alia toimidazo[1,2-b]pyridazines.

WO 2007/147646 A1 (Bayer Schering Pharma AG) relates to oxo-substitutedimidazo[1,2-b]pyridazines as kinase inhibitors, particularly PKC(protein kinase C) inhibitors, in particular PKC theta inhibitors.

WO 2008/025822 A1 (Cellzome (UK) Ltd.) relates to diazolodiazinederivatives as kinase inhibitors. In particular, WO 2008/025822 A1relates inter alia to imidazo[1,2-b]pyridazines as kinase inhibitors,particularly inducible T cell kinase (abbreviated to “Itk”) inhibitors.

WO 2008/030579 A2 (Biogen Idec MA Inc.) relates to modulators ofinterleukin-1 (IL-1) receptor-associated kinase (abbreviated to “IRAK”).In particular, WO 2008/030579 A2 relates inter alia toimidazo[1,2-b]pyridazines.

WO 2008/058126 A2 (Supergen, Inc.) relates inter alia toimidazo[1,2-b]pyridazine derivatives as protein kinase inhibitors,particularly PIM kinase inhibitors.

WO 2009/060197 A1 (Centro Nacional de Investigaciones Oncologicas(CNIO)) relates to imidazopyridazines as protein kinase inhibitors, suchas the PIM family kinases.

U.S. Pat. No. 4,408,047 (Merck & Co., Inc.,) relates inter alia toimidazopyridazines having a 3-amino-2-OR-propoxy substituent havingbeta-adrenergic blocking activity.

WO 03/018020 A1 (Takeda Chemical Industries, Ltd.) relates to inhibitorsagainst c-Jun N-terminal kinase, containing compounds which are, interalia, imidazo[1,2-b]-pyridazines.

WO 2008/052734 A1 (Novartis AG) relates to heterocyclic compounds asantiinflammatory agents. In particular said compounds are, inter alia,imidazo[1,2-b]pyridazines. The compounds are useful for treatingdiseases mediated by the ALK-5 and/or ALK-4 receptor, and are alsouseful for treating diseases mediated by the PI3K receptor, the JAK-2receptor and the TRK receptor.

WO 2008/072682 A1 (Daiichi Sankyo Company, Limited) relate toimidazo[1,2-b]pyridazine derivative which has an action of inhibitingTNF-alpha production, exerts an effect in a pathological model ofinflammatory disease and/or auto-immune disease.

WO 2008/079880 A1 (Alcon Research, Ltd.) relates to6-aminoimidazo[1,2-b]pyridazine analogues as Rho-kinase inhibitors forthe treatment of glaucoma and ocular hypertension.

WO 2009/091374 A2 (Amgen Inc.) relates to fused heterocyclicderiviatives. Selected compounds are effective for prophylaxis andtreatment of diseases, such as hepatocyte growth factor (“HGF”)diseases.

In J. Med. Chem., 2005, 48, 7604-7614, is an article entitled“Structural Basis of Inhibitor Specificity of the Protooncogene ProviralInsertion Site in Moloney Murine Leukemia Virus (PIM-1) Kinase”, anddiscloses, inter alia, imidazo[1,2-b]pyridazines as inhibitor structuresused in the study described therein.

In J. Med. Chem., 2010, 53, 6618-6628, is an article entitled “Discoveryof Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by aComprehensive Fragment-Oriented Virtual Screening Approach”, anddiscloses, inter alia, in Table 1., some specificimidazo[1,2-b]pyridazines as compounds identified as MKNK-1 inhibitors.

In Cancer Res Mar. 1, 2011, 71, 1849-1857 is an article entitled“Therapeutic inhibition of MAP kinase interacting kinase blockseukaryotic initiation factor 4E phosphorylation and suppresses outgrowthof experimental lung mestastases”, and discloses, inter alia, that theknown antigfungal agent Cercosporamide is an inhibitor of MKNK1.

However, the state of the art described above does not describe thespecific substituted imidazopyridazine compounds of general formula (I)of the present invention as defined herein, i.e. animidazo[1,2-b]pyridazinyl moiety, bearing:

-   -   in its 3-position, a:

-   -   in its 6-position, a group of structure:

wherein:

-   -   * indicates the point of attachment of said group with the rest        of the molecule,    -   R1 represents a linear C₁-C₆-alkyl-, a branched C₃-C₆-alkyl-, or        a C₃-C₆-cycloalkyl-group which is optionally substituted as        defined herein, and    -   R5 represents:        -   either:            -   a substituent as defined herein;        -   or:            -   together, with the nitrogen atom to which it is bound,                and with a carbon atom of R1, form a 3- to 7-membered                cyclic secondary amine group as defined herein;                or a stereoisomer, a tautomer, an N-oxide, a hydrate, a                solvate, or a salt thereof, or a mixture of same, as                described and defined herein, and as hereinafter                referred to as “compounds of the present invention”, or                their pharmacological activity.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit MKNK-1 kinase and may therefore beused for the treatment or prophylaxis of diseases of uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses or diseaseswhich are accompanied with uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by MKNK-1 kinase, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and

-   R1 represents a linear C₁-C₆-alkyl-, a branched C₃-C₆-alkyl-, or a    C₃-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂,    —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,    —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,    —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,    —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group;-   R2 represents a hydrogen atom;-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′,    —C(═O)N(R′)R″, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,    —N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,    —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,    —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′,    —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″ group;-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,    C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-    optionally substituted one or more times, independently from each    other, with an R substituent; heteroaryl- optionally substituted one    or more times, independently from each other, with an R substituent;    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″ group;-   R represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to    10-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″group;-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group;-   R5 represents:-   either:    -   a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,        C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,        —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group;        or:    -   together, with the nitrogen atom to which it is bound, and with        a carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group, which is optionally substituted with a substituent        selected from:        -   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,            C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,            —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,            —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,            —N(H)S(═O)R′, —N(R′)S(═O)R′, N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,            —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-,            —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH,            C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,            —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group;-   n represents an integer of 0, 1, 2, 3, 4 or 5;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom, preferably afluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl,iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- oriso-propyl group.

The term “halo-C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomerthereof.

The term “halo-C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood as preferablymeaning a linear or branched, saturated, monovalent alkyl group, asdefined supra, in which one or more of the hydrogen atoms is replaced,in identically or differently, by a C₁-C₆-alkoxy group, as definedsupra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl,butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl,pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which theterm “C₁-C₆-alkyl” is defined supra, or an isomer thereof.

The term “halo-C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood aspreferably meaning a linear or branched, saturated, monovalentC₁-C₆-alkoxy-C₁-C₆-alkyl group, as defined supra, in which one or moreof the hydrogen atoms is replaced, in identically or differently, by ahalogen atom. Particularly, said halogen atom is F. Saidhalo-C₁-C₆-alkoxy-C₁-C₆-alkyl group is, for example, —CH₂CH₂OCF₃,—CH₂CH₂OCHF₂, —CH₂CH₂OCH₂F, —CH₂CH₂OCF₂CF₃, or —CH₂CH₂OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₂-C₆-alkynyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains one ormore triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkynyl”). Said C₂-C₆-alkynylgroup is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group isethynyl, prop-1-ynyl, or prop-2-inyl.

The term “C₃-C₁₀-cycloalkyl” is to be understood as meaning a saturated,monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5,6, 7, 8, 9 or 10 carbon atoms (“C₃-C₁₀-cycloalkyl”). SaidC₃-C₁₀-cycloalkyl group is for example, a monocyclic hydrocarbon ring,e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring,e.g. a perhydropentalenylene or decalin ring. Particularly, said ringcontains 3, 4, 5 or 6 carbon atoms (“C₃-C₆-cycloalkyl”).

The term “C₄-C₁₀-cycloalkenyl” is to be understood as preferably meaninga monovalent, mono-, or bicyclic hydrocarbon ring which contains 4, 5,6, 7, 8, 9 or 10 carbon atoms and one, two, three or four double bonds,in conjugation or not, as the size of said cycloalkenyl ring allows.Said C₄-C₁₀-cycloalkenyl group is for example, a monocyclic hydrocarbonring, e.g. a cyclobutenyl, cyclopentenyl, or cyclohexenyl or a bicyclichydrocarbon, e.g.:

The term “3- to 10-membered heterocycloalkyl”, is to be understood asmeaning a saturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl- orhalo-C₁-C₆-alkyl-group; it being possible for said heterocycloalkylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3,4, or 5 carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “3- to 6-membered heterocycloalkyl”),more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms,and one or more of the above-mentioned heteroatom-containing groups (a“5- to 6-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanylring, for example. Optionally, said heterocycloalkyl can be benzo fused.

Said heterocyclyl can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. ahexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclicring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.

As mentioned supra, said nitrogen atom-containing ring can be partiallyunsaturated, i.e. it can contain one or more double bonds, such as,without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “4- to 10-membered heterocycloalkenyl”, is to be understood asmeaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl- orhalo-C₁-C₆-alkyl-group; it being possible for said heterocycloalkenylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom. Examples of saidheterocycloalkenyl may contain one or more double bonds, e.g.4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl,[1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl,2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl,4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group, or, it may be benzofused.

The term “3- to 7-membered cyclic secondary amine group”, is to beunderstood as meaning a group selected from:

wherein:

-   Rx represents a hydrogen atom, a C₁-C₆-alkyl- or    halo-C₁-C₆-alkyl-group; and-   * indicates the point of attachment of said group with the rest of    the molecule.

The term “aryl” is to be understood as preferably meaning a monovalent,aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbonring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C₆-C₁₄-aryl” group), particularly a ring having 6 carbon atoms (a“C₆-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ringhaving 9 carbon atoms (a “C₉-aryl” group), e.g. an indanyl or indenylgroup, or a ring having 10 carbon atoms (a “C₁₀-aryl” group), e.g. atetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13carbon atoms, (a “C₁₃-aryl” group), e.g. a fluorenyl group, or a ringhaving 14 carbon atoms, (a “C₁₄-aryl” group), e.g. an anthranyl group.

The term “heteroaryl” is understood as preferably meaning a monovalent,monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and in addition ineach case can be benzocondensed. Particularly, heteroaryl is selectedfrom thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof,such as, for example, benzofuranyl, benzothienyl, benzoxazolyl,benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl,isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, etc., and benzo derivatives thereof, such as, for example,quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl,purinyl, etc., and benzo derivatives thereof; or cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, or oxepinyl, etc.

In general, and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of “C₁-C₆-haloalkyl”or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkenyl” and“C₂-C₆-alkynyl”, is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

The compounds of the present invention may contain sulphur atoms whichare asymmetric, such as an asymmetric sulphoxide or sulphoximine group,of structure:

for example, in which * indicates atoms to which the rest of themolecule can be bound.Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention may be achieved by any suitable state of the art method, suchas chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt.

Said salt may be any salt, either an organic or inorganic addition salt,particularly any pharmaceutically acceptable organic or inorganicaddition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In accordance with a second embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and

-   R1 represents a linear C₁-C₆-alkyl-, a branched C₃-C₆-alkyl-, or a    C₃-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂,    —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,    —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,    —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,    —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group;-   R2 represents a hydrogen atom;-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-group;-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,    C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-    optionally substituted one or more times, independently from each    other, with an R substituent; heteroaryl- optionally substituted one    or more times, independently from each other, with an R substituent;    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″ group;-   R represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to    10-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″group;-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group;-   R5 represents:-   either:    -   a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,        C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,        —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group;-   or:    -   together, with the nitrogen atom to which it is bound and with a        carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group, which is optionally substituted with a substituent        selected from:        -   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,            C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,            —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,            —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,            —N(H)S(═O)R′, —N(R′)S(═O)R′, N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,            —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-,            —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH,            C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,            —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group;-   n represents an integer of 0, 1, 2, 3, 4 or 5;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a third embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and

-   R1 represents a linear C₁-C₆-alkyl-, a branched C₃-C₆-alkyl-, or a    C₃-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂,    —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,    —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,    —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,    —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group;-   R2 represents a hydrogen atom;-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-group;-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group;-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group;-   R5 represents:-   either:    -   a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,        C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,        —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group;-   or:    -   together, with the nitrogen atom to which it is bound and with a        carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group;-   n represents an integer of 0 or 1;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a fourth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and

-   R1 represents a linear C₁-C₅-alkyl-, a branched C₃-C₅-alkyl-, or a    C₄-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a C₁-C₆-alkyl- or an aryl-group;-   R2 represents a hydrogen atom;-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-group;-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group;-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group;-   R5 represents:-   either:    -   a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,        C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,        —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group;-   or:    -   together, with the nitrogen atom to which it is bound and with a        carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group;-   n represents an integer of 0 or 1;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a fifth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and

-   R1 represents a linear C₁-C₅-alkyl-group which is optionally    substituted, once with a substituent which is:-   an aryl-group;-   R2 represents a hydrogen atom;-   R3 represents a substituent selected from:-   a halogen atom, a C₁-C₆-alkoxy-group; R4 represents a hydrogen atom;    R5 represents:    either:    -   a substituent selected from a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-group;        or:    -   together, with the nitrogen atom to which it is bound and with a        carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group;-   n represents an integer of 0 or 1;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R1 represents a linear C₁-C₆-alkyl-, a branched C₃-C₆-alkyl-, or a    C₃-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂,    —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,    —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,    —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,    —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R2 represents a hydrogen atom.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′,    —C(═O)N(R′)R″, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,    —N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,    —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,    —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′,    —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,    C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-    optionally substituted one or more times, independently from each    other, with an R substituent; heteroaryl- optionally substituted one    or more times, independently from each other, with an R substituent;    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,    C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to    10-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′,    —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,    —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,    —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,    —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂,    —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,    —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,    —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,    —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,    —S(═O)(═NR′)R″group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R5 represents:    -   a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,        C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,        —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R5 represents:    -   together, with the nitrogen atom to which it is bound, and with        a carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group, which is optionally substituted with a substituent        selected from:        -   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,            C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, aryl-,            —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,            —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,            —N(H)S(═O)R′, —N(R′)S(═O)R′, N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,            —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-,            —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH,            C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,            —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   n represents an integer of 0, 1, 2, 3, 4 or 5.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R3 represents a substituent selected from:-   a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,    C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-group;

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R4 represents a substituent selected from:-   a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-,    C₁-C₆-haloalkyl, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R5 represents:    -   together, with the nitrogen atom to which it is bound and with a        carbon atom of R1, form a 3- to 7-membered cyclic secondary        amine group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   n represents an integer of 0 or 1.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R1 represents a linear C₁-C₅-alkyl-, a branched C₃-C₅-alkyl-, or a    C₄-C₆-cycloalkyl group which is optionally substituted, one or more    times, independently from each other, with a substituent selected    from:-   a C₁-C₆-alkyl- or an aryl-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R1 represents a linear C₁-C₅-alkyl-group which is optionally    substituted, once with a substituent which is:-   an aryl-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R3 represents a substituent selected from:-   a halogen atom, a C₁-C₆-alkoxy-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R4 represents a hydrogen atom.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R′ and R″ represent, independently from each other, a substituent    selected from:-   a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   R5 represents:    -   a substituent selected from a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-,        C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   n represents an integer of 0.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

-   n represents an integer of 1.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), according to any of theabove-mentioned embodiments, in the form of or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I), particularly in themethod described herein. In particular, the present invention coverscompounds of general formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group or a nonafluorobutylsulfonate group, forexample.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group for example, for the preparation of acompound of general formula (I) as defined supra.

EXPERIMENTAL SECTION

The following table lists the abbreviations used in this paragraph, andin the examples section.

Abbreviation Meaning DMF dimethyl formamide DMSO dimethyl sulfoxide THFtetrahydrofurane NMR nuclear magnetic resonance MS mass spectroscopyR_(t) retention time HPLC, LC high performance liquid chromatography Hhour min minute

Syntheses of Compounds (Overview)

The compounds of the present invention can be prepared as described inthe following section. Scheme 1 and the procedures described belowillustrate general synthetic routes to the compounds of general formula(I) of the invention and are not intended to be limiting. It is clear tothe person skilled in the art that the order of transformations asexemplified in Scheme 1 can be modified in various ways. The order oftransformations exemplified in the Scheme 1 is therefore not intended tobe limiting. In addition, interconversion of any of the substituents,R1, R2, R3, R4, R5 and A, can be achieved before and/or after theexemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,exchange, reduction or oxidation of functional groups, halogenation,metallation, substitution or other reactions known to the person skilledin the art. These transformations include those which introduce afunctionality which allows for further interconversion of substituents.Appropriate protecting groups and their introduction and cleavage arewell-known to the person skilled in the art (see for example T. W.Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis,3^(rd) edition, Wiley 1999). Specific examples are described in thesubsequent paragraphs. Further, it is possible that two or moresuccessive steps may be performed without work-up being performedbetween said steps, e.g. a “one-pot” reaction, as is well-known to theperson skilled in the art.

in which A, R1 R2, R3, R4, R5 and n are as defined supra, and X and Yrepresent a leaving group, such as a halogen atom, for example achlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group forexample, such as a trifluoromethylsulfonate group, anonafluorobutylsulfonate group, for example.

In the first step, a compound of formula A, i.e. a dichloropyridazinebearing suitable X substituents, can be reacted with ammonia at elevatedtemperature and pressure to give a compound of general formula B. [inanalogy to WO200733080, which is hereby incorporated herein in itsentirety as reference]

In the second step, a compound of general formula B reacts, for example,with chloroacetaldehyde or bromoacetaldehyde diacetal to give thebicyclic ring system C [in analogy to DE102006029447, which is herebyincorporated herein in its entirety as reference].

Activation of position 3 of the bicyclic system to give compounds ofgeneral formula D can be accomplished, for example, by bromination oriodination of compounds of general formula C using N-bromo-succinimideor N-iodo-succinimide, respectively.

In the fourth step, introduction of residue A-[R3]_(n) can be achievedusing suitably catalyzed cross-coupling reactions employing, forexample, boronic acids or stannanes, which results in compounds ofgeneral formula E.

Compounds of general formula E serve as central intermediates for theintroduction of various side chains containing an alcohol function,which results in imidazopyridazinyl-ethers of general formula (I).Introduction of the side chains can be achieved, for example, byemploying bases such as sodium hydride. Depending on the nature of theside chain it may be necessary to run these reactions at elevatedtemperatures. It may also be necessary to introduce side chains bearingsuitable protecting groups on functional groups which may disturb thedesired reaction.

The fourth and the fifth step of the described sequence may also beinterconverted as illustrated in Scheme 2.

In accordance with an embodiment, the present invention also relates toa method of preparing a compound of general formula (I) as definedsupra, said method comprising the step of allowing an intermediatecompound of general formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group, a nonafluorobutylsulfonate group, forexample, to react with a compound of general formula (III):

in which R1 and R5 are as defined for the compound of general formula(I), supra, thereby giving a compound of general formula (I):

in which A, R1, R2, R3, R4, R5 and n are as defined supra.

General Part

Chemical names were generated using ACD/Name Batch Version 12.01.

HPLC Methods:

Method 1:

Instrument: Waters Acquity UPLCMS ZQ4000; Column: Acquity UPLC BEH C181.7 μm, 50×2.1 mm; eluent A: water+0.05 vol % formic acid, Eluent B:acetonitrile+0.05 vol % formic acid gradient: 0-1.6 min 1-99% B, 1.6-2.0min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DADscan: 210-400 nm; ELSD

Method 2:

Instrument: Waters Acquity UPLCMS SQD 3001; Column: Acquity UPLC BEH C181.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (95%), eluentB: acetonitrile, gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm;ELSD

Method 3:

Instrument: Waters Acquity UPLCMS SQD; Column: Acquity UPLC BEH C18 1.7μm, 50×2.1 mm; eluent A: water+0.05 vol % formic acid (95%), eluent B:acetonitrile+0.05 vol % formic acid (95%), gradient: 0-1.6 min 1-99% B,1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2μL; DAD scan: 210-400 nm; ELSD

Method 4:

Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1.750×2.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B:acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8mL/min; temperature: 60° C.; injection: 2 μl; DAD scan: 210-400 nm; ELSD

INTERMEDIATES Intermediate 1 3-Bromo-6-chloro-imidazo[1,2-b]pyridazine

3-Bromo-6-chloro-imidazo[1,2-b]pyridazine was synthesised as describedfor example in WO 2007/147646 or DE 10 2006 029447, e.g. as follows:

Step 1: Preparation of 6-Chloroimidazo[1,2-b]pyridazine

5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated togetherwith 4.7 mL (40 mmol) of chloracetaldehyde (55% strength in water) in 15mL of n-butanol at 120° C. for a period of 5 days. After the reactionwas complete, the reaction mixture was added to saturated sodiumbicarbonate solution and extracted three times with ethyl acetate. Thecombined organic phases were then washed with sat. sodium chloridesolution and dried over sodium sulfate, and the solvent was removed invacuo. In the final purification by chromatography on silica gel, 4.17 g(70%) of the desired product were isolated in the form of an amorphouswhite solid.

¹H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (1H); 7.79 (1H); 7.92 (1H); 7.96(1H).

Step 2: Preparation of 3-Bromo-6-chloroimidazo[1,2-b]pyridazine

478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introducedinto 10 mL of chloroform under argon and, while cooling in ice, 664 mg(3.73 mmol) of N-bromosuccuinimide were added. After the addition wascomplete, the reaction mixture was stirred at room temperatureovernight. The reaction mixture was then mixed with water and ethylacetate and, after addition of saturated sodium bicarbonate solution,the phases were separated. The aqueous phase was extracted three moretimes with ethyl acetate. The combined organic phases were then washedwith sat. sodium chloride solution and dried over sodium sulfate. In thefinal removal of the solvent in vacuo, the desired product was isolatedin quantitative yield in the form of an amorphous white solid which wasemployed without further chromatographic purification in subsequentreactions.

¹H-NMR (CHLOROFORM-d): δ [ppm]=7.12 (1H); 7.79 (1H); 7.90 (1H).

Intermediate 2 3-(1-Benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine

13.9 g (59.8 mmol) 3-bromo-6-chloro-imidazo[1,2-b]pyridazine weresuspended in 508 mL 1,4-dioxane. 10.1 g (62.8 mmol)2-benzofuranylboronic acid, 2.76 g (2.29 mmol)tetrakis(triphenylphosphino)palladium-(0) and 90 mL (180 mmol) of a 2Maqueous sodium carbonate solution were added. The obtained mixture washeated to 100° C. for 24 h.

400 mL of a saturated aqueous ammonium chloride solution were added. Theobtained mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine and dried over magnesium sulfate. Afterevaporation of the solvent, the obtained solid material was digested in40 mL of a mixture of dichloromethane and methanol (8:2), filtered offand dried in vacuo to yield 5.42 g (44%) of the title compound as solidmaterial.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=7.23-7.40 (2H), 7.51 (1H), 7.59-7.67(2H), 7.77 (1H), 8.33-8.40 (2H).

LCMS (Method 1): R_(t)=1.35 min; MS (ESIpos) m/z=270 [M+H]⁺.

Intermediate 36-Chloro-3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(4-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wasprepared in analogy to3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine starting from 1.68g (7.22 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine to yield 43%of a solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.96 (3H), 6.85-6.91 (1H), 7.25-7.38(2H), 7.52-7.59 (2H), 8.37-8.43 (2H)

LCMS (Method 1): R_(t)=1.31 min; MS (ESIpos) m/z=300 [M+H]⁺.

Intermediate 46-Chloro-3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wasprepared in analogy to3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine starting from 1.74g (7.5 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine to yield 45% ofa solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.81 (3H), 6.91-6.99 (1H), 7.33 (1H),7.50-7.60 (3H), 8.35-8.42 (2H).

LCMS (Method 1): R_(t)=1.29 min; MS (ESIpos) m/z=300 [M+H]⁺.

Intermediate 56-Chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

Step 1: A mixture of 2 g (13 mmol) 7-chloro-1-benzofuran in dry THF (100mL) was cooled to −78° C. 7.9 ml (19.7 mmol) of a solution ofn-butyllithium in hexane was added and the resulting mixture was stirredfor 1 h at −78° C. 5.3 mL (19.7 mmol) of tributyltin chloride was added.The reaction was stirred at room temperature over night.

Methanol was carefully added and the solvent evaporated. The obtainedresidue was purified by flash chromatography to yield 6.2 g of crudeproduct of the corresponding 2-stannylbenzofurane, which was usedwithout further purification in step 2.

Step 2: In an inert atmosphere, 2.34 g (10.1 mmol) of3-bromo-6-chloro-imidazo[1,2-b]pyridazine, 5.79 g (13.1 mmol) of thecrude 2-stannylbenzofurane from step 1, 192 mg (1 mmol) copper (I)iodide and 354 mg (0.5 mmol) bis(triphenylphosphine)palladium(II)chloride in 100 mL of THF is stirred for 19 h at 85° C. ina sealed pressure tube. The solvent was evaporated, the obtained solidwas digested in methanol and filtered off to yield 2.73 g of the titlecompound as solid material which was used as crude product in thesubsequent reactions.

LCMS (Method 3): R_(t)=1.00 min; MS (ESIpos) m/z=304 [M+H]⁺.

Intermediate 66-Chloro-3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wasprepared in analogy to6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine startingfrom 513 mg (2.21 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine toyield 166 mg of a solid material (approx. 57% pure). This material wasused in subsequent steps without further purification

LCMS (Method 4): R_(t)=1.37 min; MS (ESIpos) m/z=288 [M+H]+.

Intermediate 76-Chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wasprepared in analogy to6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine startingfrom 921 mg (3.96 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine toyield 929 mg of a solid material which was used as crude product.

1H-NMR (300 MHz, DMSO-d₆), δ [ppm]=7.09-7.23 (1H), 7.32-7.45 (1H), 7.55(3H), 8.41 (2H).

LCMS (Method 3): Rt=1.42 min; MS (ESIpos) m/z=288 [M+H]+.

EXAMPLES Example 13-(1-Benzofuran-2-yl)-6-[2-(morpholin-2-yl)ethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 68.1 mg (0.52 mmol) 2-(2-morpholinyl)ethanol were addedto 18.3 mg (0.46 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 70mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for72 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 45 mg (47%)product as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.86-1.96 (2H), 2.40 (1H), 2.56-2.68(2H), 2.82 (1H), 3.43 (1H), 3.52-3.60 (1H), 3.73 (1H), 4.53-4.60 (2H),7.01 (1H), 7.24-7.35 (2H), 7.59-7.65 (2H), 7.67-7.74 (1H), 8.10-8.18(2H).

LC-MS (Method 3): R_(t)=0.78 min; MS (ESIpos) m/z=365 [M+H]⁺.

Example 23-(4-Methoxy-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 191 mg (1.6 mmol) (R)-2-hydroxymethylmorpholine wereadded to 64 mg (1.6 mmol) sodium hydride (60% in mineral oil) in 24 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,120 mg (0.4 mmol)6-chloro-3-(4-methoxy-1-benzofuran-2-yl)-imidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for24 h at room temperature.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to yield 21 mg (14%) product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.63-2.73 (3H), 2.95 (1H), 3.48 (1H),3.77 (1H), 3.92 (4H), 4.41 (2H), 6.83 (1H), 7.04 (1H), 7.19-7.33 (2H),7.53 (1H), 8.02-8.18 (2H).

LC-MS (Method 3): R_(t)=0.81 min; MS (ESIpos) m/z=381 [M+H]⁺.

Example 33-(1-Benzofuran-2-yl)-6-(morpholin-2-ylmethoxy)imidazo[1,2-b]pyridazine

Step 1: In an ice bath, 2.0 g (8.9 mmol) tert.-butyl2-(hydroxymethyl)morpholine-4-carboxylate were added to 188 mg (7.83mmol) sodium hydride (60% in mineral oil) in 24 mL anhydroustetrahydrofurane. After 15 min of stirring in the ice bath, 1.2 g (4.45mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and the reaction mixture was stirred for 4 daysat room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloridesolution, and extracted with ethyl acetate. The combined organic phaseswere washed with brine, dried over magnesium sulfate, and concentrated.The obtained crude product (3.3 g) was used without further purificationin step 2.

Step 2: To 2.2 g of the crude product from step 1 in 36 mLdichloromethane were added 8.9 mL of trifluoroacetic acid. The mixturewas stirred for 3 h. Aqueous ammonia was added until the mixture reachedbasic pH. Brine was added and the mixture extracted withdichloromethane. The organic layer was separated, dried over magnesiumsulfate and concentrated. 1.68 g of a solid material were obtained ascrude product.

A small sample (75 mg) were purified by HPLC to give 18 mg of theproduct as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.64-2.75 (3H), 2.94-3.02 (1H), 3.51(1H), 3.76-3.92 (1H), 4.45 (2H), 7.06 (1H), 7.23-7.37 (2H), 7.60-7.66(1H), 7.72 (1H), 8.12-8.19 (2H).

LC-MS (Method 3): R_(t)=0.81 min; MS (ESIpos) m/z=381 [M+H]⁺.

Example 4N-(3-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propyl)-2,2-dimethylpropan-1-amine

In an ice bath, 75 mg (0.52 mmol)(3-[(2,2-dimethylpropyl)amino]propan-1-ol were added to 18 mg (0.45mmol) sodium hydride (60% in mineral oil) in 4 mL anhydroustetrahydrofurane. After 15 min of stirring in the ice bath, 70 mg (0.26mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and the reaction mixture was stirred for 16 hat 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 56 mg (57%)product as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=0.83 (9H), 1.93-2.02 (2H), 2.26 (2H),2.72 (2H), 4.56 (2H), 7.00 (1H), 7.24-7.35 (2H), 7.58 (1H), 7.60-7.64(1H), 7.66-7.70 (1H), 8.13 (2H).

LC-MS (Method 4): R_(t)=0.90 min; MS (ESIpos) m/z=379 [M+H]⁺.

Example 53-(5-Methoxy-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 191 mg (1.6 mmol) (R)-2-hydroxymethylmorpholine wereadded to 64 mg (1.6 mmol) sodium hydride (60% in mineral oil) in 3 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,120 mg (0.40 mmol)6-chloro-3-(5-methoxy-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for24 h at room temperature.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to yield 20 mg (13%) product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.66-2.71 (3H), 2.87-2.96 (1H),3.41-3.56 (1H), 3.79 (5H), 4.42 (2H), 6.90 (1H), 7.04 (1H), 7.24 (1H),7.48-7.58 (2H), 8.06-8.19 (2H).

LC-MS (Method 3): R_(t)=0.83 min; MS (ESIpos) m/z=381 [M+H]⁺.

Example 62-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(cyclopropylmethyl)ethanamine

In an ice bath, 87 mg (0.74 mmol) 2-[(cyclopropylmethyl)amino]ethan-1-olwere added to 26 mg (0.65 mmol) sodium hydride (60% in mineral oil) in 5mL anhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,100 mg (0.37 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 16 h at 40° C.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to yield 56 mg (43%) product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=0.08-0.17 (2H), 0.34-0.45 (2H),0.85-0.98 (1H), 2.54 (2H), 3.11 (2H), 4.58 (2H), 7.03 (1H), 7.23-7.37(2H), 7.59-7.66 (2H), 7.71 (1H), 8.12-8.23 (2H).

LC-MS (Method 4): R_(t)=0.82 min; MS (ESIpos) m/z=349 [M+H]⁺.

Example 73-(1-Benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 355 mg (2.97 mmol) (R)-2-hydroxymethylmorpholine wereadded to 119 mg (2.97 mmol) sodium hydride (60% in mineral oil) in 6 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,200 mg (0.74 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 24 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to yield 67 mg (25%) product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.62-2.73 (3H), 2.92-3.02 (1H),3.43-3.57 (1H), 3.72-3.93 (2H), 4.44 (2H), 7.05 (1H), 7.21-7.40 (2H),7.59-7.66 (2H), 7.70-7.75 (1H), 8.12-8.20 (2H).

LC-MS (Method 3): R_(t)=0.78 min; MS (ESIpos) m/z=351 [M+H]⁺.

Example 83-(1-Benzofuran-2-yl)-6-{2-[(3R)-morpholin-3-yl]ethoxy}imidazo[1,2-b]pyridazine

In an ice bath, 68 mg (0.52 mmol) 2-[(3R)-morpholin-3-yl]ethanol wereadded to 18 mg (0.45 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 70mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for15 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by flash chromatography to yield38 mg (40%) product as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.81 (2H), 2.70-2.78 (2H), 2.85-2.95(1H), 3.11 (1H), 3.34-3.38 (1H), 3.65 (1H), 3.76 (1H), 4.59 (2H), 7.04(1H), 7.27-7.38 (2H), 7.62-7.68 (2H), 7.73 (1H), 8.16 (2H).

LC-MS (Method 3): R_(t)=0.73 min; MS (ESIpos) m/z=365 [M+H]⁺.

Example 93-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(propan-2-yl)propan-1-amine

In an ice bath, 89 mg (0.74 mmol) 3-(propan-2-ylamino)propan-1-ol wereadded to 26 mg (0.65 mmol) sodium hydride (60% in mineral oil) in 5 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,100 mg (0.37 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 16 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and ethyl acetate was added. The resulting precipitate wasfiltered off, washed with water and ethyl acetate and dried in vacuum togive 124 mg (95%) of the product as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.23 (6H), 2.19-2.29 (2H), 3.11 (2H),4.61 (2H), 7.03 (1H), 7.24-7.36 (2H), 7.60-7.65 (1H), 7.67 (1H),7.71-7.76 (1H), 8.14-8.21 (2H).

LC-MS (Method 2): R_(t)=0.85 min; MS (ESIpos) m/z=351 [M+H]⁺.

Example 10N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)propan-2-amine

In an ice bath, 78 mg (0.74 mmol) 2-(isopropylamino)ethan-1-ol wereadded to 26 mg (0.65 mmol) sodium hydride (60% in mineral oil) in 5 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,100 mg (0.37 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 16 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to yield 65 mg (46%) product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.00 (6H), 3.00 (2H), 3.39 (1H), 4.53(2H), 6.96-7.06 (1H), 7.23-7.36 (2H), 7.59-7.66 (2H), 7.68-7.74 (1H),8.12-8.18 (2H).

LC-MS (Method 4): R_(t)=0.80 min; MS (ESIpos) m/z=337 [M+H]⁺.

Example 113-(1-Benzofuran-2-yl)-6-[(2S)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 355 mg (2.97 mmol) (S)-2-hydroxymethylmorpholine wereadded to 119 mg (2.97 mmol) sodium hydride (60% in mineral oil) in 6 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,200 mg (0.74 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 24 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated to give 280 mg of a crudeproduct. 49 mg of the crude product were purified by HPLC to yield 2 mgproduct as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.64-2.72 (3H), 2.94 (1H), 3.42-3.54(1H), 3.72-3.89 (2H), 4.44 (2H), 7.06 (1H), 7.23-7.36 (2H), 7.60-7.65(2H), 7.73 (1H), 8.12-8.20 (2H).

LC-MS (Method 3): R_(t)=0.76 min; MS (ESIpos) m/z=351 [M+H]⁺.

Example 12N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)-2,2-dimethylpropan-1-amine

In an ice bath, 68 mg (0.52 mmol) 2-[(2,2-dimetyhlpropyl)amino]ethanolwere added to 18 mg (0.46 mmol) sodium hydride (60% in mineral oil) in 4mL anhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,70 mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 72 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 50 mg (53%)product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=0.84 (9H), 2.35 (2H), 3.01 (2H), 4.55(2H), 7.03 (1H), 7.23-7.36 (2H), 7.62 (2H), 7.67-7.72 (1H), 8.11-8.17(2H).

LC-MS (Method 4): R_(t)=0.89 min; MS (ESIpos) m/z=365 [M+H]⁺.

Example 133-(1-Benzofuran-2-yl)-6-{2-[(3S)-morpholin-3-yl]ethoxy}imidazo[1,2-b]pyridazine

In an ice bath, 96 mg (0.52 mmol) (S)-2-(morpholin-3-yl)ethanol wereadded to 18 mg (0.46 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 70mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for15 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by flash chromatography to yield51 mg (54%) product as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.81 (2H), 2.73-2.80 (2H), 2.86-2.95(1H), 3.12 (1H), 3.33-3.40 (1H), 3.65 (1H), 3.76 (1H), 4.59 (2H), 7.03(1H), 7.27-7.38 (2H), 7.62-7.67 (2H), 7.70-7.75 (1H), 8.16 (2H).

LC-MS (Method 3): R_(t)=0.74 min; MS (ESIpos) m/z=365 [M+H]⁺.

Example 146-(Azetidin-3-ylmethoxy)-3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazine

In an ice bath, 64 mg (0.52 mmol) 3-(hydroxymethyl)azetidinehydrochloride were added to 41 mg (1.04 mmol) sodium hydride (60% inmineral oil) in 4 mL anhydrous tetrahydrofurane. After 15 min ofstirring in the ice bath, 70 mg (0.26 mmol)3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added. The icebath was removed and the reaction mixture was stirred for 72 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 39 mg (46%)product as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.18 (1H), 3.50-3.60 (2H), 3.66-3.77(2H), 4.63 (2H), 7.03 (1H), 7.22-7.37 (2H), 7.60-7.66 (2H), 7.70-7.76(1H), 8.12-8.19 (2H).

LC-MS (Method 3): R_(t)=0.74 min; MS (ESIpos) m/z=321 [M+H]⁺.

Example 153-(1-Benzofuran-2-yl)-6-{2-[(2S)-pyrrolidin-2-yl]ethoxy}imidazo[1,2-b]pyridazine

Step 1: To 9.3 g (40.4 mmol)[(2S)-1-(tert.-butoxycarbonyl)pyrrolidin-2-yl]acetic acid in 116 mLtetrahydrofurane were added dropwise 40 mL of borane-dimethyl sulfidecomplex. The resulting mixture was stirred for 2 h at 80° C.

The mixture was carefully poured into saturated aqueous sodiumhydrogencarbonate solution. The aqueous layer was extracted withmethyl-tert.-butylether. The combined organic layers were washed withbrine, dried over magnesium sulfate, and concentrated to give 6.2 g of acrude product which was used without further purification in step 2.

Step 2: In an ice bath, 1.37 g (6.39 mmol) of the crude product fromstep 1 were added to 224 mg (5.62 mmol) sodium hydride (60% in mineraloil) in 34 mL anhydrous tetrahydrofurane. After 15 min of stirring inthe ice bath, 861 mg (3.19 mmol)3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added. The icebath was removed and the reaction mixture was stirred for 24 h at roomtemperature.

The reaction mixture was poured into saturated aqueous ammoniumchloridesolution, and extracted with ethyl acetate. The combined organic phaseswere washed with brine, dried over magnesium sulfate, and concentrated.The obtained crude product (2.1 g) was used without further purificationin step 3.

Step 3: To 1.4 g of the crude product from step 2 in 28 mLdichloromethane were added 4.9 mL of trifluoroacetic acid. The mixturewas stirred for 1 h. Aqueous sodium hydroxide solution was added untilthe mixture reached basic pH. Brine was added and the mixture extractedwith dichloromethane. The organic layer was separated, dried overmagnesium sulfate and concentrated.

The residue was purified by HPLC to give 725 mg of the product as solidmaterial.

1H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.57-1.72 (1H), 1.77-2.01 (2H),2.11-2.32 (3H), 3.09-3.24 (2H), 3.64 (1H), 4.51-4.70 (2H), 7.02 (1H),7.24-7.37 (2H), 7.60-7.66 (2H), 7.67-7.74 (1H), 8.13-8.23 (2H).

LC-MS (Method 1): R_(t)=0.82 min; MS (ESIpos) m/z=349 [M+H]⁺.

Example 163-(1-Benzofuran-2-yl)-6-(piperidin-2-ylmethoxy)imidazo[1,2-b]pyridazine

Step 1: In an ice bath, 1.95 g (8.9 mmol) tert.-butyl2-(hydroxymethyl)piperidine-1-carboxylate were added to 313 mg (7.83mmol) sodium hydride (60% in mineral oil) in 24 mL anhydroustetrahydrofurane. After 15 min of stirring in the ice bath, 1.2 g (4.45mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and the reaction mixture was stirred for 4 daysat room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloridesolution, and extracted with ethyl acetate. The combined organic phaseswere washed with brine, dried over magnesium sulfate, and concentrated.The obtained crude product (1.65 g) was used without furtherpurification in step 2.

Step 2: To the crude product from step 1 in 36 mL dichloromethane wereadded 8.9 mL of trifluoroacetic acid. The mixture was stirred for 3 h.Aqueous ammonia was added until the mixture reached basic pH. Brine wasadded and the mixture extracted with dichloromethane. The organic layerwas separated, dried over magnesium sulfate and concentrated.

The residue was purified by HPLC to give 358 mg (23%) of the product assolid material.

¹H-NMR (500 MHz, DMSO-d₆), δ [ppm]=1.32-1.49 (3H), 1.62 (1H), 1.84 (2H),2.66-2.71 (1H), 3.09 (1H), 3.17 (1H), 4.40-4.45 (1H), 4.46-4.51 (1H),7.07 (1H), 7.30-7.35 (1H), 7.36-7.40 (1H), 7.65 (1H), 7.66-7.69 (1H),7.74-7.78 (1H), 8.19-8.23 (2H).

LC-MS (Method 1): R_(t)=0.82 min; MS (ESIpos) m/z=349 [M+H]⁺.

Example 17N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)cyclopropanamine

In an ice bath, 77 mg (0.74 mmol) 2-(cyclopropylamino)ethan-1-ol wereadded to 26 mg (0.65 mmol) sodium hydride (60% in mineral oil) in 5 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,100 mg (0.37 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 16 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was digested inmethanol to give 25 mg (20%) of the title compound as a solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=0.70-0.94 (4H), 2.82 (1H), 3.58 (2H),4.81 (2H), 7.04 (1H), 7.24-7.38 (2H), 7.61-7.67 (2H), 7.71 (1H),8.17-8.25 (2H).

LC-MS (Method 2): R_(t)=0.82 min; MS (ESIpos) m/z=335 [M+H]⁺.

Example 18N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)-2-methylpropan-2-amine

In an ice bath, 61 mg (0.52 mmol) 2-(tert.-butylamino)ethan-1-ol wereadded to 18.3 mg (0.46 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 70mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for72 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was digested in methyl-tert.-butylether togive 73 mg (80%) of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.05 (9H), 2.96 (2H), 4.49 (2H), 7.02(1H), 7.24-7.35 (2H), 7.62 (2H), 7.68-7.73 (1H), 8.11-8.16 (2H).

LC-MS (Method 4): R_(t)=0.82 min; MS (ESIpos) m/z=351 [M+H]⁺.

Example 192-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(propan-2-yl)propan-1-amine

In an ice bath, 61 mg (0.52 mmol) 1-(isopropylamino)propan-2-ol wereadded to 18.3 mg (0.46 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 70mg (0.26 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for16 h at 40° C.

The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 52 mg (57%) ofthe title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=0.97 (6H), 1.46 (3H), 2.74-2.84 (2H),2.96 (1H), 5.25-5.35 (1H), 6.97 (1H), 7.24-7.35 (2H), 7.59 (1H), 7.62(1H), 7.71 (1H), 8.14 (2H).

LC-MS (Method 4): R_(t)=0.84 min; MS (ESIpos) m/z=351 [M+H]⁺.

Example 203-(5-Chloro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 189 mg (1.58 mmol) (R)-2-hydroxymethylmorpholine wereadded to 63 mg (1.58 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,120 mg (0.4 mmol)6-chloro-3-(5-chloro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for16 h at room temperature.

The reaction mixture was poured into saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was digested inmethanol to give 15 mg (10%) of the title compound as a solid material.

1H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.57-2.72 (3H), 2.93 (1H), 3.48 (1H),3.73-3.88 (2H), 4.42 (2H), 7.07 (1H), 7.33 (1H), 7.59 (1H), 7.66 (1H),7.80 (1H), 8.13-8.19 (2H).

LC-MS (Method 3): R_(t)=0.88 min; MS (ESIpos) m/z=385 [M+H]⁺.

Example 213-(1-Benzofuran-2-yl)-6-[(2R)-pyrrolidin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 5 g (49.4 mmol) (R)-2-(hydroxymethyl)pyrrolidine wereadded to 2.97 g (74.2 mmol) sodium hydride (60% in mineral oil) in 466mL anhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,6.67 g (24.7 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 16 h at 40° C.

The reaction mixture was carefully poured into brine, and extracted withethyl acetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by flash chromatography to give5.6 g (68%) of the title compound as a solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.46-2.13 (4H), 2.73-2.89 (2H),3.45-3.57 (1H), 4.26-4.33 (2H), 6.96-7.02 (1H), 7.29 (2H), 7.55 (1H),7.61 (1H), 7.69-7.75 (1H), 8.12 (2H).

LC-MS (Method 3): R_(t)=0.79 min; MS (ESIpos) m/z=335 [M+H]⁺.

Example 223-(1-Benzofuran-2-yl)-6-(piperidin-3-yloxy)imidazo[1,2-b]pyridazine

In an ice bath, 5 g (49.4 mmol) piperidine-3-ol were added to 2.96 g(74.2 mmol) sodium hydride (60% in mineral oil) in 500 mL anhydroustetrahydrofurane. After 15 min of stirring in the ice bath, 6.67 g (24.7mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and the reaction mixture was stirred for 12hours at 40° C.

The reaction mixture was carefully poured into brine, and extracted withethyl acetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was digested in ethyl acetate to give 5.5 g(60%) of the title compound as a solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.54-1.83 (3H), 2.23-2.32 (1H),2.54-2.63 (1H), 2.75 (1H), 2.81-2.89 (1H), 3.33 (2H), 5.06 (1H), 7.00(1H), 7.27-7.39 (2H), 7.54 (1H), 7.63-7.67 (1H), 7.72-7.76 (1H),8.13-8.18 (2H).

LC-MS (Method 3): R_(t)=0.80 min; MS (ESIpos) m/z=335 [M+H]⁺.

Example 233-(1-Benzofuran-2-yl)-6-[(2S)-pyrrolidin-2-ylmethoxy]imidazo[1,2-b]pyridazine

In an ice bath, 5 g (49.4 mmol) (S)-2-hydroxymethylpyrrolidine wereadded to 2.96 g (74.2 mmol) sodium hydride (60% in mineral oil) in 466mL anhydrous tetrahydrofurane. After 15 min of stirring in the ice bath,6.67 g (24.7 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazinewere added. The ice bath was removed and the reaction mixture wasstirred for 12 h at 40° C.

The reaction mixture was carefully poured into brine, and extracted withethyl acetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by flash chromatography to give6.1 g (62%) of the title compound as solid material.

¹H NMR (300 MHz, DMSO-d₆) δ [ppm]=1.83-2.21 (4H), 3.40-3.56 (2H),3.58-3.80 (2H), 4.17 (1H), 4.63-5.21 (1H), 7.03 (1H), 7.21-7.41 (2H),7.49-7.79 (3H), 7.88-8.07 (2H).

LC-MS (Method 3): R_(t)=0.78 min; MS (ESIpos) m/z=335 [M+H]⁺.

Example 241-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methylpropan-2-amine

At 0-5° C. 132 mg (1.48 mmol) 2-(methylamino)propan-1-ol were added to59.3 mg (1.48 mmol) sodium hydride (60% in mineral oil) in 7.5 mLanhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred 1.5 h at room temperature.

The reaction mixture was poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 107.6 mg (45%)product.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.21 (3H), 2.43 (3H), 3.15-3.28 (1H),4.46 (2H), 7.02 (1H), 7.23-7.37 (2H), 7.57-7.65 (2H), 7.69 (1H),8.11-8.20 (2H).

LC-MS (Method 2): R_(t)=0.83 min; MS (ESIpos) m/z=323 [M+H]⁺.

Example 253-(5-Chloro-1-benzofuran-2-yl)-6-{2-[(2S)-pyrrolidin-2-yl]ethoxy}imidazo[1,2-b]pyridazine

Step 1: To 9.3 g (40.4 mmol)[(2S)-1-(tert.-butoxycarbonyl)pyrrolidin-2-yl]acetic acid in 116 mLtetrahydrofurane were added dropwise 40 mL of borane-dimethyl sulfidecomplex. The resulting mixture was stirred for 2 h at 80° C.

The mixture was carefully poured into saturated aqueous sodiumhydrogencarbonate solution. The aqueous layer was extracted withmethyl-tert.-butylether. The combined organic layers were washed withbrine, dried over magnesium sulfate, and concentrated to give 6.2 g of acrude product which was used without further purification in step 2.

Step 2: In an ice bath, 150 mg (0.7 mmol) of the crude product from step1 were added to 37 mg (0.93 mmol) sodium hydride (60% in mineral oil) in6 mL anhydrous tetrahydrofurane. After 15 min of stirring in the icebath, 189 mg (0.47 mmol)3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added. The icebath was removed and the reaction mixture was stirred for 18 h at roomtemperature.

The reaction mixture was poured into water, and extracted with ethylacetate. The combined organic phases were dried over sodium sulfate, andconcentrated. The obtained crude product (327 mg) was used withoutfurther purification in step 3.

Step 3: To 327 mg of the crude product from step 2 in 5.8 mLdichloromethane were added 1.3 mL of trifluoroacetic acid. The mixturewas stirred for 1.5 h. Aqueous ammonia was added until the mixturereached basic pH. Brine was added and the mixture extracted withdichloromethane. The organic layer was separated, dried over magnesiumsulfate and concentrated.

The residue was purified by HPLC to give 45 mg (17%) of the product assolid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.38-1.53 (1H), 1.67-1.86 (2H),1.95-2.12 (3H), 2.87-3.06 (2H), 3.31-3.43 (2H), 4.60 (2H), 7.02-7.10(1H), 7.33-7.41 (1H), 7.67 (2H), 7.79-7.85 (1H), 8.15-8.23 (2H).

LC-MS (Method 3): R_(t)=0.90 min; MS (ESIpos) m/z=383 [M+H]⁺.

Example 262-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methylpropan-1-amine

At 0-5° C. 132 mg (1.48 mmol) 1-(methylamino)propan-2-ol were added to59.3 mg (1.48 mmol) sodium hydride (60% in mineral oil) in 7.5 mLanhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred 1.5 h at room temperature.

The reaction mixture was poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 21 mg (9%)product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.45 (3H), 2.36 (3H), 2.80-2.87 (1H),2.90-2.98 (1H), 5.33-5.43 (1H), 6.96 (1H), 7.24-7.36 (2H), 7.58 (1H),7.60-7.65 (1H), 7.68-7.74 (1H), 8.14 (2H).

LC-MS (Method 2): R_(t)=0.83 min; MS (ESIpos) m/z=323 [M+H]⁺.

Example 27 Formicacid-N-(2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)propan-2-amine(1:1)

At 0-5° C. 199 mg (1.11 mmol) 2-(isopropylamino)-1-phenylethanol wereadded to 44.5 mg (1.11 mmol) sodium hydride (60% in mineral oil) in 7.5mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred 3 h at room temperature. Thereaction mixture was poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 105 mg (41%)product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.05 (6H), 2.86-2.97 (1H), 3.00-3.07(1H), 3.18-3.26 (1H), 6.11-6.16 (1H), 7.17 (1H), 7.25-7.44 (6H), 7.61(3H), 7.75-7.81 (2H), 8.11 (1H), 8.17-8.24 (2H).

LC-MS (Method 2): R_(t)=0.98 min; MS (ESIpos) m/z=413 [M+H]⁺.

Example 28N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)-2-methylpropan-1-amine

At 0-5° C. 215 mg (1.11 mmol) 2-(isobutylamino)-1-phenylethanol wereadded to 44.5 mg (1.11 mmol) sodium hydride (60% in mineral oil) in 7.5mL anhydrous DMF. After 5 min of stirring on the ice bath, 150 mg (0.56mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred 1.5 h at room temperature.The reaction mixture was poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 101 mg (43%)product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=0.84 (6H), 1.61-1.72 (1H), 2.45 (2H),2.93-3.00 (1H), 3.12-3.20 (1H), 6.09-6.15 (1H), 7.16 (1H), 7.24-7.43(6H), 7.60 (3H), 7.74-7.79 (1H), 8.10 (1H), 8.18 (1H).

LC-MS (Method 2): R_(t)=1.11 min; MS (ESIpos) m/z=427 [M+H]⁺.

Example 29(-)-2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methyl-2-phenylethanamine

At 0-5° C. 56 mg (0.371 mmol) racemic 2-(methylamino)-1-phenylethanolwere added to 7.4 mg (0.185 mmol) sodium hydride (60% in mineral oil) in2.5 mL anhydrous DMF. After 30 min of stirring on the ice bath, 50 mg(0.185 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine wereadded. The ice bath was removed and it was stirred 3 h at roomtemperature.

The reaction mixtures were poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 44 mg (62%)product.

LC-MS (Method 2): R_(t)=0.99 min; MS (ESIpos) m/z=385 [M+H]⁺.

The enantiomers were separated by chiral HPLC (Chiralpak IA 5 μm, 250×30mm, Hexan/Ethanol 90:10+0.1% diethylamine, 40 mL/min).

Peak1: 20 mg, α=−432.2° (1.00; CHCl₃)

¹H-NMR (300 MHz, CHLOROFORM-d), δ [ppm]=2.55 (3H), 3.04 (1H), 3.28 (1H),6.16 (1H), 6.90 (1H), 7.18 (1H), 7.24-7.35 (3H), 7.40 (2H), 7.48-7.57(3H), 7.63 (1H), 7.90 (1H), 8.09 (1H).

Example 30N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)-2,2-dimethylpropan-1-amine

At 0-5° C. 361.6 mg (1.48 mmol)2-[(2,2-dimethylpropyl)amino]-1-phenylethanol hydrochloride were addedto 118.6 mg (2.97 mmol) sodium hydride (60% in mineral oil) in 10 mLanhydrous DMF. After 5 min of stirring on the ice bath, 200 mg (0.74mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred 1.5 h at room temperature.The reaction mixture was poured into half saturated ammonium chloridesolution, and extracted four times with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to yield 186 mg (57%)product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=0.83 (9H), 2.41 (2H), 2.94-3.02 (1H),3.14-3.23 (1H), 6.09-6.16 (1H), 7.17 (1H), 7.24-7.44 (6H), 7.60 (3H),7.74-7.79 (1H), 8.10 (1H), 8.19 (1H).

LC-MS (Method 2): R_(t)=1.03 min; MS (ESIpos) m/z=441 [M+H]⁺.

Example 313-(1-Benzofuran-2-yl)-6-[(3R)-pyrrolidin-3-yloxy]imidazo[1,2-b]pyridazine

At 0-5° C. 1.551 g (17.80 mmol) (3R)-pyrrolidin-3-ol were added to 712mg (17.80 mmol) sodium hydride (60% in mineral oil) in 60 mL anhydrousDMF. After 5 min of stirring on the ice bath, 2.4 g (8.90 mmol)3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added. The icebath was removed and it was stirred over night at room temperature. Thereaction mixture was poured into saturated ammonium chloride solution,and extracted ten times with 100 mL chloroform. The combined organicphases were dried over magnesium sulfate, and concentrated. The crudematerial was combined with a second batch with the same amount under thesame conditions. The residue was purified on silica gel withdichloromethane and methanol. The collected fractions were concentratedand digested in 2-isopropoxypropane. The solid was filtered off, washedwith diethyl ether and dried under vacuum over the weekend at roomtemperature to yield 2.55 g (43%) product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.90-1.99 (1H), 2.15-2.26 (1H),2.79-2.88 (1H), 2.89-2.98 (1H), 2.99-3.05 (1H), 3.22-3.26 (1H, and watersignal), 5.50-5.56 (1H), 6.97 (1H), 7.24-7.35 (2H), 7.58-7.65 (2H), 7.74(1H), 8.08-8.17 (2H).

LC-MS (Method 2): R_(t)=0.81 min; MS (ESIpos) m/z=321 [M+H]⁺.

[α]=62.5°, (methanol, 0.28)

Example 323-(1-Benzofuran-2-yl)-6-[(3R)-piperidin-3-yloxy]imidazo[1,2-b]pyridazine

At 0-5° C. 200 mg (1.45 mmol) (3R)-piperidin-3-ol hydrochloride wereadded to 116.3 mg (2.91 mmol) sodium hydride (60% in mineral oil) in 7mL anhydrous DMF. After 5 min of stirring on the ice bath, 196 mg (0.73mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine were added.The ice bath was removed and it was stirred over night at roomtemperature. The reaction mixture was poured into saturated ammoniumchloride solution, and extracted four times with ethyl acetate. Thecombined organic phases were washed twice with brine, dried overmagnesium sulfate, and concentrated. The crude material was treated with5 mL DMSO. The solid was filtered off and washed with water. It wasdried at 45° C. and vacuum yielding 155 mg (63%) product.

¹H-NMR (400 MHz, CHLOROFORM-d), δ [ppm]=1.69 (1H), 1.85-2.03 (2H),2.22-2.32 (1H), 2.84-2.92 (1H), 2.92-3.00 (1H), 3.10 (1H), 3.35 (1H),5.14-5.22 (1H), 6.80 (1H), 7.24-7.36 (2H, and chloroform signal), 7.45(1H), 7.55 (1H), 7.65 (1H), 7.90 (1H), 8.18 (1H).

LC-MS (Method 2): R_(t)=0.78 min; MS (ESIpos) m/z=335 [M+H]⁺.

Example 333-(4-Fluoro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]-pyridazine

In an ice bath, 51 mg (0.43 mmol) (2R)-morpholin-2-ylmethanol were addedto 17 mg (0.43 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 74mg (0.22 mmol)6-chloro-3-(4-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for18 h at 40° C.

The reaction mixture was carefully poured into water, and extracted withethyl acetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by HPLC to give 49 mg (55%) ofthe title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.54-2.72 (3H), 2.94 (1H), 3.42-3.54(1H), 3.77 (1H), 3.82-3.91 (1H), 4.43 (2H), 7.03-7.17 (2H), 7.35 (1H),7.52 (1H), 7.58 (1H), 8.14-8.20 (2H).

LC-MS (Method 4): R_(t)=0.81 min; MS (ESIpos) m/z=369 [M+H]⁺.

Example 343-(5-Fluoro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]-pyridazine

In an ice bath, 33 mg (0.29 mmol) (2R)-morpholin-2-ylmethanol were addedto 12 mg (0.29 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous tetrahydrofurane. After 15 min of stirring in the ice bath, 69mg (0.14 mmol)6-chloro-3-(5-fluoro-1-benzofuran-2-yl)imidazo[1,2-b]pyridazine wereadded. The ice bath was removed and the reaction mixture was stirred for18 h at 40° C.

The reaction mixture was carefully poured into saturated aqueousammonium chloride solution, and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, and concentrated. Theresidue was purified by HPLC to give 14 mg (24%) of the title compoundas solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=2.65-2.77 (3H), 2.99 (1H), 3.47-3.55(1H), 3.80 (1H), 3.83-3.91 (1H), 4.44 (2H), 7.04-7.10 (1H), 7.15 (1H),7.53 (1H), 7.60 (1H), 7.65 (1H), 8.14-8.19 (2H).

LC-MS (Method 4): R_(t)=0.82 min; MS (ESIpos) m/z=369 [M+H]⁺.

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science aTechnology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science a Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science a Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

-   acidifying agents (examples include but are not limited to acetic    acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);-   alkalinizing agents (examples include but are not limited to ammonia    solution, ammonium carbonate, diethanolamine, monoethanolamine,    potassium hydroxide, sodium borate, sodium carbonate, sodium    hydroxide, triethanolamine, trolamine);-   adsorbents (examples include but are not limited to powdered    cellulose and activated charcoal);-   aerosol propellants (examples include but are not limited to carbon    dioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃) air displacement agents    (examples include but are not limited to nitrogen and argon);-   antifungal preservatives (examples include but are not limited to    benzoic acid, butylparaben, ethylparaben, methylparaben,    propylparaben, sodium benzoate);-   antimicrobial preservatives (examples include but are not limited to    benzalkonium chloride, benzethonium chloride, benzyl alcohol,    cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl    alcohol, phenylmercuric nitrate and thimerosal);-   antioxidants (examples include but are not limited to ascorbic acid,    ascorbyl palmitate, butylated hydroxyanisole, butylated    hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl    gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde    sulfoxylate, sodium metabisulfite);-   binding materials (examples include but are not limited to block    polymers, natural and synthetic rubber, polyacrylates,    polyurethanes, silicones, polysiloxanes and styrene-butadiene    copolymers);-   buffering agents (examples include but are not limited to potassium    metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate    anhydrous and sodium citrate dihydrate)-   carrying agents (examples include but are not limited to acacia    syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup,    orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,    bacteriostatic sodium chloride injection and bacteriostatic water    for injection)-   chelating agents (examples include but are not limited to edetate    disodium and edetic acid)-   colourants (examples include but are not limited to FD&C Red No. 3,    FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No.    5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);-   clarifying agents (examples include but are not limited to    bentonite);-   emulsifying agents (examples include but are not limited to acacia,    cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,    sorbitan monooleate, polyoxyethylene 50 monostearate);-   encapsulating agents (examples include but are not limited to    gelatin and cellulose acetate phthalate) flavourants (examples    include but are not limited to anise oil, cinnamon oil, cocoa,    menthol, orange oil, peppermint oil and vanillin);-   humectants (examples include but are not limited to glycerol,    propylene glycol and sorbitol);-   levigating agents (examples include but are not limited to mineral    oil and glycerin);-   oils (examples include but are not limited to arachis oil, mineral    oil, olive oil, peanut oil, sesame oil and vegetable oil);-   ointment bases (examples include but are not limited to lanolin,    hydrophilic ointment, polyethylene glycol ointment, petrolatum,    hydrophilic petrolatum, white ointment, yellow ointment, and rose    water ointment);-   penetration enhancers (transdermal delivery) (examples include but    are not limited to monohydroxy or polyhydroxy alcohols, mono- or    polyvalent alcohols, saturated or unsaturated fatty alcohols,    saturated or unsaturated fatty esters, saturated or unsaturated    dicarboxylic acids, essential oils, phosphatidyl derivatives,    cephalin, terpenes, amides, ethers, ketones and ureas)-   plasticizers (examples include but are not limited to diethyl    phthalate and glycerol);-   solvents (examples include but are not limited to ethanol, corn oil,    cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid,    peanut oil, purified water, water for injection, sterile water for    injection and sterile water for irrigation);-   stiffening agents (examples include but are not limited to cetyl    alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl    alcohol, white wax and yellow wax);-   suppository bases (examples include but are not limited to cocoa    butter and polyethylene glycols (mixtures));-   surfactants (examples include but are not limited to benzalkonium    chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl    sulfate and sorbitan mono-palmitate);-   suspending agents (examples include but are not limited to agar,    bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl    cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,    kaolin, methylcellulose, tragacanth and veegum);-   sweetening agents (examples include but are not limited to    aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin    sodium, sorbitol and sucrose);-   tablet anti-adherents (examples include but are not limited to    magnesium stearate and talc);-   tablet binders (examples include but are not limited to acacia,    alginic acid, carboxymethylcellulose sodium, compressible sugar,    ethylcellulose, gelatin, liquid glucose, methylcellulose,    non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch);-   tablet and capsule diluents (examples include but are not limited to    dibasic calcium phosphate, kaolin, lactose, mannitol,    microcrystalline cellulose, powdered cellulose, precipitated calcium    carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);-   tablet coating agents (examples include but are not limited to    liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose,    hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,    cellulose acetate phthalate and shellac);-   tablet direct compression excipients (examples include but are not    limited to dibasic calcium phosphate);-   tablet disintegrants (examples include but are not limited to    alginic acid, carboxymethylcellulose calcium, microcrystalline    cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone,    sodium alginate, sodium starch glycollate and starch);-   tablet glidants (examples include but are not limited to colloidal    silica, corn starch and talc);-   tablet lubricants (examples include but are not limited to calcium    stearate, magnesium stearate, mineral oil, stearic acid and zinc    stearate);-   tablet/capsule opaquants (examples include but are not limited to    titanium dioxide);-   tablet polishing agents (examples include but are not limited to    carnuba wax and white wax);-   thickening agents (examples include but are not limited to beeswax,    cetyl alcohol and paraffin);-   tonicity agents (examples include but are not limited to dextrose    and sodium chloride);-   viscosity increasing agents (examples include but are not limited to    alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,    methylcellulose, polyvinyl pyrrolidone, sodium alginate and    tragacanth); and-   wetting agents (examples include but are not limited to    heptadecaethylene oxycetanol, lecithins, sorbitol monooleate,    polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

-   Sterile IV Solution: A 5 mg/mL solution of the desired compound of    this invention can be made using sterile, injectable water, and the    pH is adjusted if necessary. The solution is diluted for    administration to 1-2 mg/mL with sterile 5% dextrose and is    administered as an IV infusion over about 60 min.-   Lyophilised powder for IV administration: A sterile preparation can    be prepared with (i) 100-1000 mg of the desired compound of this    invention as a lyophilised powder, (ii) 32-327 mg/mL sodium citrate,    and (iii) 300-3000 mg Dextran 40. The formulation is reconstituted    with sterile, injectable saline or dextrose 5% to a concentration of    10 to 20 mg/mL, which is further diluted with saline or dextrose 5%    to 0.2-0.4 mg/mL, and is administered either IV bolus or by IV    infusion over 15-60 min.-   Intramuscular suspension: The following solution or suspension can    be prepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

-   Hard Shell Capsules: A large number of unit capsules are prepared by    filling standard two-piece hard galantine capsules each with 100 mg    of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose    and 6 mg of magnesium stearate.-   Soft Gelatin Capsules: A mixture of active ingredient in a    digestible oil such as soybean oil, cottonseed oil or olive oil is    prepared and injected by means of a positive displacement pump into    molten gelatin to form soft gelatin capsules containing 100 mg of    the active ingredient. The capsules are washed and dried. The active    ingredient can be dissolved in a mixture of polyethylene glycol,    glycerin and sorbitol to prepare a water miscible medicine mix.-   Tablets: A large number of tablets are prepared by conventional    procedures so that the dosage unit is 100 mg of active ingredient,    0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate,    275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg    of lactose. Appropriate aqueous and non-aqueous coatings may be    applied to increase palatability, improve elegance and stability or    delay absorption.-   Immediate Release Tablets/Capsules: These are solid oral dosage    forms made by conventional and novel processes. These units are    taken orally without water for immediate dissolution and delivery of    the medication. The active ingredient is mixed in a liquid    containing ingredient such as sugar, gelatin, pectin and sweeteners.    These liquids are solidified into solid tablets or caplets by freeze    drying and solid state extraction techniques. The drug compounds may    be compressed with viscoelastic and thermoelastic sugars and    polymers or effervescent components to produce porous matrices    intended for immediate release, without the need of water.

Combination Therapies

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known chemotherapeutic agents or anti-cancer agents, e.g.anti-hyper-proliferative or other indication agents, and the like, aswell as with admixtures and combinations thereof. Other indicationagents include, but are not limited to, anti-angiogenic agents, mitoticinhibitors, alkylating agents, anti-metabolites, DNA-intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymeinhibitors, toposisomerase inhibitors, biological response modifiers, oranti-hormones.

The term “chemotherapeutic anti-cancer agents”, includes but is notlimited to

-   131l-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,    alemtuzumab, alitretinoin, altretamine, aminoglutethimide,    amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide,    asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394,    BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab,    bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib,    buserelin, busulfan, cabazitaxel, calcium folinate, calcium    levofolinate, capecitabine, carboplatin, carmofur, carmustine,    catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil,    chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid,    clofarabine, crisantaspase, cyclophosphamide, cyproterone,    cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib,    daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab,    deslorelin, dibrospidium chloride, docetaxel, doxifluridine,    doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab,    elliptinium acetate, eltrombopag, endostatin, enocitabine,    epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin,    eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus,    exemestane, fadrozole, filgrastim, fludarabine, fluorouracil,    flutamide, formestane, fotemustine, fulvestrant, gallium nitrate,    ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin,    histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds,    ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide,    imatinib, imiquimod, improsulfan, interferon alfa, interferon beta,    interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide,    lapatinib, lenalidomide, lenograstim, lentinan, letrozole,    leuprorelin, levamisole, lisuride, lobaplatin, lomustine,    lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,    mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl    aminolevulinate, methyltestosterone, mifamurtide, miltefosine,    miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin,    mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib,    nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab,    omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel,    palifermin, palladium-103 seed, pamidronic acid, panitumumab,    pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin    beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed,    pentazocine, pentostatin, peplomycin, perfosfamide, picibanil,    pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol    phosphate, polysaccharide-K, porfimer sodium, pralatrexate,    prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed,    ranimustine, razoxane, regorafenib, risedronic acid, rituximab,    romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran,    sobuzoxane, sodium glycididazole, sorafenib, streptozocin,    sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin,    teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin,    temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin,    thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab,    topotecan, toremifene, tositumomab, trabectedin, trastuzumab,    treosulfan, tretinoin, trilostane, triptorelin, trofosfamide,    tryptophan, ubenimex, valrubicin, vandetanib, vapreotide,    vemurafenib, vinblastine, vincristine, vindesine, vinflunine,    vinorelbine, vorinostat, vorozole, yttrium-90 glass microspheres,    zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon.alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin-prostate cancer, Javelin-melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131l-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (I) as defined herein can optionally beadministered in combination with one or more of the following: ARRY-162,ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226,BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201,enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980,GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027,perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167,RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine,UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemotherapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit MKNK-1 and may thereforebe used for the treatment or prophylaxis of diseases of uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses, ordiseases which are accompanied with uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses, particularly in whichthe uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses is mediated by MKNK-1, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I), described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by MKNK-1, such as, forexample, haematological tumours, solid tumours, and/or metastasesthereof, e.g. leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumours,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assays:

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

MKNK1 Kinase Assay

MKNK1-inhibitory activity of compounds of the present invention wasquantified employing the MKNK1 TR-FRET assay as described in thefollowing paragraphs.

A recombinant fusion protein of Glutathione-S-Transferase (GST,N-terminally) and human full-length MKNK1 (amino acids 1-424 and T344Dof accession number BAA 19885.1), expressed in insect cells usingbaculovirus expression system and purified via glutathione sepharoseaffinity chromatography, was purchased from Carna Biosciences (productno 02-145) and used as enzyme. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amideform) was used which can be purchased e.g. form the company Biosyntan(Berlin-Buch, Germany).

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofMKNK1 in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM magnesiumchloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (Sigma)] wasadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc.in the 5 μL assay volume is 10 μM) and substrate (0.1 μM=>final conc. inthe 5 μL assay volume is 0.06 μM) in assay buffer and the resultingmixture was incubated for a reaction time of 45 min at 22° C. Theconcentration of MKNK1 was adjusted depending of the activity of theenzyme lot and was chosen appropriate to have the assay in the linearrange, typical concentrations were in the range of 0.05 μg/mL. Thereaction was stopped by the addition of 5 μL of a solution of TR-FRETdetection reagents (5 nM streptavidine-XL665 [Cisbio Bioassays, Codolet,France] and 1 nM anti-ribosomal protein S6 (pSer236)-antibody fromInvitrogen [#44921G] and 1 nM LANCE EU-W1024 labeled ProteinG[Perkin-Elmer, product no. AD0071]) in an aqueous EDTA-solution (100 mMEDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22° C. to allow theformation of complex between the phosphorylated biotinylated peptide andthe detection reagents. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the Eu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm were measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit.

TABLE 1 MKNK1 IC₅₀s Example MKNK1 IC₅₀ [nM] 1 4 3 4 4 4 6 7 8 6 9 7 10 811 12 12 11 13 9 15 12 16 16 17 8 18 24 19 16 21 15 22 25 23 25 25 39 2736 28 59 29 98 30 227 31 22 32 28 33 10 34 10

MKNK1 Kinase High ATP Assay

MKNK1-inhibitory activity at high ATP of compounds of the presentinvention after their preincubation with MKNK1 was quantified employingthe TR-FRET-based MKNK1 high ATP assay as described in the followingparagraphs.

A recombinant fusion protein of Glutathione-S-Transferase (GST,N-terminally) and human full-length MKNK1 (amino acids 1-424 and T344Dof accession number BAA 19885.1), expressed in insect cells usingbaculovirus expression system and purified via glutathione sepharoseaffinity chromatography, was purchased from Carna Biosciences (productno 02-145) and used as enzyme. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amideform) was used, which can be purchased e.g. from the company Biosyntan(Berlin-Buch, Germany).

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofMKNK1 in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mM magnesiumchloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40 (Sigma)] wasadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μL of a solution of adenosine-tri-phosphate (ATP, 3.3 mM=>final conc.in the 5 μL assay volume is 2 mM) and substrate (0.1 μM=>final conc. inthe 5 μL assay volume is 0.06 μM) in assay buffer and the resultingmixture was incubated for a reaction time of 30 min at 22° C. Theconcentration of MKNK1 was adjusted depending of the activity of theenzyme lot and was chosen appropriate to have the assay in the linearrange, typical concentrations were in the range of 0.003 μg/mL. Thereaction was stopped by the addition of 5 μL of a solution of TR-FRETdetection reagents (5 nM streptavidine-XL665 [Cisbio Bioassays, Codolet,France] and 1 nM anti-ribosomal protein S6 (pSer236)-antibody fromInvitrogen [#44921G] and 1 nM LANCE EU-W1024 labeled ProteinG[Perkin-Elmer, product no. AD0071]) in an aqueous EDTA-solution (100 mMEDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22° C. to allow theformation of complex between the phosphorylated biotinylated peptide andthe detection reagents. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the Eu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm were measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (e.g. 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series preparedseparately before the assay on the level of the 100 fold concentratedsolutions in DMSO by serial dilutions, the exact concentrations may varydepending on the pipettor used) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit.

TABLE 2 MKNK1 high ATP IC₅₀s Example MKNK1 high ATP IC₅₀ [nM] 1 6 2 11 312 4 13 5 18 6 18 7 19 8 20 9 20 10 23 11 24 12 25 13 25 14 27 15 30 1632 17 36 18 37 19 38 20 41 21 44 22 53 23 53 24 55 25 91 26 93 27 75 28114 29 124 30 239 31 49 32 53 33 15 34 11

CDK2/CycE Kinase Assay

CDK2/CycE-inhibitory activity of compounds of the present invention wasquantified employing the CDK2/CycE TR-FRET assay as described in thefollowing paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchased fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofCDK2/CycE in aqueous assay buffer [50 mM Tris/hydrochloric acid pH 8.0,10 mM magnesium chloride, 1.0 mM dithiothreitol, 0.1 mM sodiumortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μL of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μL assay volume is 10 μM) and substrate (1.25 μM=>final conc. in the 5μL assay volume is 0.75 μM) in assay buffer and the resulting mixturewas incubated for a reaction time of 25 min at 22° C. The concentrationof CDK2/CycE was adjusted depending of the activity of the enzyme lotand was chosen appropriate to have the assay in the linear range,typical concentrations were in the range of 130 ng/mL. The reaction wasstopped by the addition of 5 μL of a solution of TR-FRET detectionreagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays, Codolet, France]and 1 nM anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389]and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer,product no. AD0077, as an alternative a Terbium-cryptate-labeledanti-mouse IgG antibody from Cisbio Bioassays can be used]) in anaqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovine serum albumin in100 mM HEPES/sodium hydroxide pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC50 values were calculated by a 4 parameter fit.

PDGFRI3 Kinase Assay

PDGFRI3 inhibitory activity of compounds of the present invention wasquantified employing the PDGFRI3 HTRF assay as described in thefollowing paragraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman PDGFRβ (amino acids 561-1106, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated poly-Glu,Tyr (4:1) copolymer (#61GT0BLA) from CisBiointernational (Marcoule, France) was used.

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofPDGFRβ in aqueous assay buffer [50 mM HEPES/sodium hydroxide pH 7.5, 10mM magnesium chloride, 2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100(Sigma)] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7μM=>final conc. in the 5 μL assay volume is 10 μM) and substrate (2.27μg/mL=>final conc. in the 5 μL assay volume is 1.36 μg/mL [˜30 nM]) inassay buffer and the resulting mixture was incubated for a reaction timeof 25 min at 22° C. The concentration of PDGFRβ in the assay wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, typical enzymeconcentrations were in the range of about 125 pg/μL (final conc. in the5 μL assay volume). The reaction was stopped by the addition of 5 μL ofa solution of HTRF detection reagents (200 nM streptavidine-XLent [CisBiointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelatelabelled anti-phospho-tyrosine antibody from Perkin Elmer [instead ofthe PT66-Eu-chelate PT66-Tb-Cryptate from Cis Biointernational can alsobe used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 50 mM HEPES/sodium hydroxide pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XLentand the PT66-Eu-Chelate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

Fyn Kinase Assay

C-terminally His6-tagged human recombinant kinase domain of the humanT-Fyn expressed in baculovirus infected insect cells (purchased fromInvitrogen, P3042) was used as kinase. As substrate for the kinasereaction the biotinylated peptide biotin-KVEKIGEGTYGW (C-terminus inamid form) was used which can be purchased e.g. form the companyBiosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofT-Fyn in aqueous assay buffer [25 mM Tris/hydrochloric acid pH 7.2, 25mM magnesium chloride, 2 mM dithiothreitol, 0.1% (w/v) bovine serumalbumin, 0.03% (v/v) Nonidet-P40 (Sigma)]. were added and the mixturewas incubated for 15 min at 22° C. to allow pre-binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5 μL assayvolume is 10 μM) and substrate (2 μM=>final conc. in the 5 μL assayvolume is 1.2 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofFyn was adjusted depending of the activity of the enzyme lot and waschosen appropriate to have the assay in the linear range, typicalconcentration was 0.13 nM. The reaction was stopped by the addition of 5μL of a solution of HTRF detection reagents (0.2 μM streptavidine-XL[Cisbio Bioassays, Codolet, France) and 0.66 nM PT66-Eu-Chelate, aneuropium-chelate labelled anti-phospho-tyrosine antibody from PerkinElmer [instead of the PT66-Eu-chelate PT66-Tb-Cryptate from CisbioBioassays can also be used]) in an aqueous EDTA-solution (125 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES/sodium hydroxide pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL andthe PT66-Eu-Chelate. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from thePT66-Eu-Chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Normally test compounds were tested on the samemicrotiter plate at 10 different concentrations in the range of 20 μM to1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1nM and 1 nM, dilution series prepared before the assay at the level ofthe 100fold conc. stock solutions by serial 1:3 dilutions) in duplicatevalues for each concentration and IC₅₀ values were calculated by a 4parameter fit.

Flt4 Kinase Assay

Flt4 inhibitory activity of compounds of the present invention wasquantified employing the Flt4 TR-FRET assay as described in thefollowing paragraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman Flt4 (amino acids 799-1298, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated peptide Biotin- Ahx-GGEEEEYFELVKKKK (C-terminus in amideform, purchased from Biosyntan, Berlin-Buch, Germany) was used.

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofFlt4 in aqueous assay buffer [25 mM HEPES pH 7.5, 10 mM magnesiumchloride, 2 mM dithiothreitol, 0.01% (v/v) Triton-X100 (Sigma), 0.5 mMEGTA, and 5 mM β-phospho-glycerol] were added and the mixture wasincubated for 15 min at 22° C. to allow pre-binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5 μL assayvolume is 10 μM) and substrate (1.67 μM=>final conc. in the 5 μL assayvolume is 1 μM) in assay buffer and the resulting mixture was incubatedfor a reaction time of 45 min at 22° C. The concentration of Flt4 in theassay was adjusted depending of the activity of the enzyme lot and waschosen appropriate to have the assay in the linear range, typical enzymeconcentrations were in the range of about 120 pg/μL (final conc. in the5 μL assay volume). The reaction was stopped by the addition of 5 μL ofa solution of HTRF detection reagents (200 nM streptavidine-XL665 [CisBiointernational] and 1 nM PT66-Tb-Cryptate, an terbium-cryptatelabelled anti-phospho-tyrosine antibody from Cisbio Bioassays (Codolet,France) in an aqueous EDTA-solution (50 mM EDTA, 0.2% (w/v) bovine serumalbumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Tb-Cryptate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

TrkA Kinase Assay

TrkA inhibitory activity of compounds of the present invention wasquantified employing the TrkA HTRF assay as described in the followingparagraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman TrkA (amino acids 443-796, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated poly-Glu, Tyr (4:1) copolymer (#61GT0BLA) from CisBiointernational (Marcoule, France) was used.

For the assay 50 nL of a 100fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of a solution ofTrkA in aqueous assay buffer [8 mM MOPS/hydrochloric acid pH 7.0, 10 mMmagnesium chloride, 1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma), 0.2mM EDTA] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7μM=>final conc. in the 5 μL assay volume is 10 μM) and substrate (2.27μg/mL=>final conc. in the 5 μL assay volume is 1.36 μg/mL [˜30 nM]) inassay buffer and the resulting mixture was incubated for a reaction timeof 60 min at 22° C. The concentration of TrkA in the assay was adjusteddepending of the activity of the enzyme lot and was chosen appropriateto have the assay in the linear range, typical enzyme concentrationswere in the range of about 20 pg/μL (final conc. in the 5 μL assayvolume). The reaction was stopped by the addition of 5 μL of a solutionof HTRF detection reagents (30 nM streptavidine-XL665 [CisBiointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelatelabelled anti-phospho-tyrosine antibody from Perkin Elmer [instead ofthe PT66-Eu-chelate PT66-Tb-Cryptate from Cis Biointernational can alsobe used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 50 mM HEPES/sodium hydroxide pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Eu-Chelate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

AlphaScreen SureFire eIF4E Ser209 Phosphorylation Assay

The AlphaScreen SureFire eIF4E Ser209 phoshorylation assay is used tomeasure the phosphorylation of endogenous eIF4E in cellular lysates. TheAlphaScreen SureFire technology allows the detection of phosphorylatedproteins in cellular lysates. In this assay, sandwich antibodycomplexes, which are only formed in the presence of the analyte (p-eIF4ESer209), are captured by AlphaScreen donor and acceptor beads, bringingthem into close proximity. The excitation of the donor bead provokes therelease of singlet oxygen molecules that triggers a cascade of energytransfer in the Acceptor beads, resulting in the emission of light at520-620 nm.

Surefire EIF4e Alphascreen in A549 Cells with 20% FCS Stimulation

For the assay the AlphaScreen SureFire p-eIF4E Ser209 10K Assay Kit andthe AlphaScreen ProteinA Kit (for 10K assay points) both from PerkinElmer were used.

On day one 50.000 A549 cells were plated in a 96-well plate in 100 μLper well in growth medium (DMEM/Hams' F12 with stable glutamine, 10%FCS) and incubated at 37° C. After attachment of the cells, medium waschanged to starving medium (DMEM, 0.1% FCS, without glucose, withglutamine, supplemented with 5 g/L maltose). On day two, test compoundswere serially diluted in 50 μL starving medium with a final DMSOconcentration of 1% and were added to A549 cells in test plates at afinal concentration range from as high 10 μM to as low 10 nM dependingon the activities of the tested compounds. Treated cells were incubatedat 37° C. for 2 h. 37 ul FCS was added to the wells (=final FCSconcentration 20%) for 20 min. Then medium was removed and cells werelysed by adding 50 μL lysis buffer. Plates were then agitated on a plateshaker for 10 min. After 10 min lysis time, 4 μL of the lysate istransferred to a 384well plate (Proxiplate from Perkin Elmer) and 5 μLReaction Buffer plus Activation Buffer mix containing AlphaScreenAcceptor beads was added. Plates were sealed with TopSeal-A adhesivefilm, gently agitated on a plate shaker for 2 h at room temperature.Afterwards 2 μL Dilution buffer with AlphaScreen Donor beads were addedunder subdued light and plates were sealed again with TopSeal-A adhesivefilm and covered with foil. Incubation takes place for further 2 hgently agitation at room temperature. Plates were then measured in anEnVision reader (Perkin Elmer) with the AlphaScreen program. Each datapoint (compound dilution) was measured as triplicate.

The IC₅₀ values were determined by means of a 4-parameter fit.

It will be apparent to persons skilled in the art that assays for otherMKNK-1 kinases may be performed in analogy using the appropriatereagents.

Thus the compounds of the present invention effectively inhibit one ormore MKNK-1 kinases and are therefore suitable for the treatment orprophylaxis of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by MKNK-1, more particularly in which the diseasesof uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses are haemotological tumours, solid tumours and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The invention claimed is:
 1. A compound of general formula (I):

in which:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and R1 represents a linear C₁-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted, one or more times, independently from each other, with asubstituent selected from: a halogen atom, a —CN, C₁-C₆-alkyl-,C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,aryl-, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,—NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″ group; R2 represents a hydrogen atom; R3represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,—C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′,—S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″ group; R4represents a substituent selected from: a hydrogen atom, a halogen atom,a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-optionallysubstituted one or more times, independently from each other, with an Rsubstituent; heteroaryl- optionally substituted one or more times,independently from each other, with an R substituent; —C(═O)NH₂,—C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″,—SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′,—S(═O)₂N(R′)R″, —S(═O)(═NR′)R″ group; R represents a substituentselected from: a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂,—C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-,—OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″group; R′ and R″ represent, independently from each other,a substituent selected from: a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-,C₁-C₆-haloalkyl group; R5 represents: either: a substituent selectedfrom a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂,—C(═O)N(H)R′, —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group; or: together,with the nitrogen atom to which it is bound, and with a carbon atom ofR1, form a 3- to 7-membered cyclic secondary amine group, which isoptionally substituted with a substituent selected from: a halogen atom,a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OH, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆ alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group; n representsan integer of 0, 1, 2, 3, 4 or 5; or a stereoisomer, a tautomer, or asalt thereof, or a mixture of same.
 2. The compound according to claim1, wherein:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and R1 represents a linear C₁-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted, one or more times, independently from each other, with asubstituent selected from: a halogen atom, a —CN, C₁-C₆-alkyl-,C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,aryl-, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,—NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″ group; R2 represents a hydrogen atom; R3represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-group; R4 represents a substituent selected from: ahydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl-optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —(═O)(═NR′)R″ group;R represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-,heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from: a C₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkylgroup; R5 represents: either: a substituent selected from aC₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂,—C(═O)N(H)R′, —C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group; or: together,with the nitrogen atom to which it is bound and with a carbon atom ofR1, form a 3- to 7-membered cyclic secondary amine group, which isoptionally substituted with a substituent selected from: a halogen atom,a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OH, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆ alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″ group; n representsan integer of 0, 1, 2, 3, 4 or 5; or a stereoisomer, a tautomer, or amixture of same.
 3. The compound according to claim 1, wherein:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and R1 represents a linear C₁-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted, one or more times, independently from each other, with asubstituent selected from: a halogen atom, a —CN, C₁-C₆-alkyl-,C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,aryl-, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′,—NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″ group; R2 represents a hydrogen atom; R3represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-group; R4 represents a substituent selected from: ahydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group; R′ and R″ represent,independently from each other, a substituent selected from: aC₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group; R5 represents:either: a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-,C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,—C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group; or: together, with thenitrogen atom to which it is bound and with a carbon atom of R1, form a3- to 7-membered cyclic secondary amine group; n represents an integerof 0 or 1; or a stereoisomer, a tautomer, or a salt thereof, or amixture of same.
 4. The compound according to claim 1, wherein:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and R1 represents a linear C₁-C₅-alkyl-, a branchedC₃-C₅-alkyl-, or a C₄-C₆-cycloalkyl group which is optionallysubstituted, one or more times, independently from each other, with asubstituent selected from: a C₁-C₆-alkyl- or an aryl-group; R2represents a hydrogen atom; R3 represents a substituent selected from: ahalogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-group; R4 represents a substituent selected from: ahydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group; R′ and R″ represent,independently from each other, a substituent selected from: aC₁-C₆-alkyl-, C₃-C₁₀-cycloalkyl-, C₁-C₆-haloalkyl group; R5 represents:either: a substituent selected from a C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-alkyl-,C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-, aryl-, —C(═O)NH₂, —C(═O)N(H)R′,—C(═O)N(R′)R″, —S(═O)R′, —S(═O)₂R′ group; or: together, with thenitrogen atom to which it is bound and with a carbon atom of R1, form a3- to 7-membered cyclic secondary amine group; n represents an integerof 0 or 1; or a stereoisomer, a tautomer, or a salt thereof, or amixture of same.
 5. The compound according to claim 1, wherein:

represents a:

wherein * indicates the point of attachment of said group with the restof the molecule; and R1 represents a linear C₁-C₅-alkyl-group which isoptionally substituted, once with a substituent which is: an aryl-group;R2 represents a hydrogen atom; R3 represents a substituent selectedfrom: a halogen atom, a C₁-C₆-alkoxy-group; R4 represents a hydrogenatom; R5 represents: either: a substituent selected from a C₁-C₆-alkyl-,C₃-C₁₀-cycloalkyl-, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl-group; or: together,with the nitrogen atom to which it is bound and with a carbon atom ofR1, form a 3- to 7-membered cyclic secondary amine group; n representsan integer of 0 or 1; or a stereoisomer, a tautomer, or a salt thereof,or a mixture of same.
 6. The compound according to claim 1, which isselected from the group consisting of:3-(1-Benzofuran-2-yl)-6-[2-(morpholin-2-yl)ethoxy]imidazo[1,2-b]pyridazine;3-(4-Methoxy-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-(morpholin-2-ylmethoxy)imidazo[1,2-b]pyridazine;N-(3-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propyl)-2,2-dimethylpropan-1-amine;3-(5-Methoxy-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine;2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(cyclopropylmethyl)ethanamine;3-(1-Benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-{2-[(3R)-morpholin-3-yl]ethoxy}imidazo[1,2-b]pyridazine;3-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(propan-2-yl)propan-1-amine;N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)propan-2-amine;3-(1-Benzofuran-2-yl)-6-[(2S)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine;N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)-2,2-dimethylpropan-1-amine;3-(1-Benzofuran-2-yl)-6-{2-[(3S)-morpholin-3-yl]ethoxy}imidazo[1,2-b]pyridazine;6-(Azetidin-3-ylmethoxy)-3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-{2-[(2S)-pyrrolidin-2-yl]ethoxy}imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-(piperidin-2-ylmethoxy)imidazo[1,2-b]pyridazine;N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)cyclopropanamine;N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}ethyl)-2-methylpropan-2-amine;2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-(propan-2-yl)propan-1-amine;3-(5-Chloro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-[(2R)-pyrrolidin-2-ylmethoxy]imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-(piperidin-3-yloxy)imidazo[1,2-b]pyridazine;3-(1-Benzofuran-2-yl)-6-[(2S)-pyrrolidin-2-ylmethoxy]imidazo[1,2-b]pyridazine;1{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methylpropan-2-amine;3-(5-Chloro-1-benzofuran-2-yl)-6-{2-[(2S)-pyrrolidin-2-yl]ethoxy}imidazo[1,2-b]pyridazine;2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methylpropan-1-amine;Formicacid-N-(2-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)propan-2-amine(1:1);N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)-2-methylpropan-1-amine;(-)-2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-N-methyl-2-phenylethanamine;N-(2-{[3-(1-Benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylethyl)-2,2-dimethylpropan-1-amine;3-(1-benzofuran-2-yl)-6-[(3R)-pyrrolidin-3-yloxy]imidazo[1,2-b]pyridazine;3-(1-benzofuran-2-yl)-6-[(3R)-piperidin-3-yloxy]imidazo[1,2-b]pyridazine;3-(4-fluoro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]-pyridazine;3-(5-fluoro-1-benzofuran-2-yl)-6-[(2R)-morpholin-2-ylmethoxy]imidazo[1,2-b]-pyridazine;a streoisomer thereof; a tautomer thereof; a salt thereof; and a mixturethereof.
 7. A method of preparing a compound according to claim 1,comprising reacting an intermediate compound of general formula (V):

in which A, R2, R3, R4 and n are as defined in claim 1, and X representsa leaving group, with a compound of general formula (III):

in which R1 and R5 are defined in claim 1, thereby giving a compound ofgeneral formula (I):

in which A, R1, R2, R3, R4, R5 and n are as defined in claim
 1. 8. Apharmaceutical composition comprising a compound of general formula (I),or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, or a mixture of same, according to claim 1, and apharmaceutically acceptable diluent or carrier.
 9. A pharmaceuticalcombination comprising: one or more first active ingredients selectedfrom compounds of general formula (I) according to claim 1, and one ormore second active ingredients selected from chemotherapeuticanti-cancer agents.